Central vision provides us high acuity essential for everyday tasks. However, central vision is highly sensitive to our metabolic state: it decreases at night and during acute hypoglycemia. Transient central scotomas can appear during severe hypoglycemia. These striking affects of acute hypoglycemia occur in part in central retina. Current analysis of a chronically hypoglycemic mouse indicates that long-term metabolic stress decreases retinal sensitivity causing late-onset progressive degeneration. This proposal will examine the metabolic and circadian modulation of vision, its underlying causes and potential consequences by investigating: Aim 1: Circadian and metabolic modulation of human vision. Aim 2: Glucose utilization and metabolic modulation in the monkey retina. Aim 3: A potential new mouse model for studying metabolic-stress induced retinal degeneration. Aim 1 studies the circadian and metabolic modulation of rod and cone vision of nondiabetics and diabetics using psychophysical (2IFC) and physiological (mERG) techniques. Glucose clamp and time of day will control metabolic state. Aim 2 studies metabolic modulation and glucose utilization in the monkey retina by measuring their mERG and retinal uptake of t 4C-2-deoxyglucose. Aim 3 will study a new mouse model made hypoglycemic by a null mutation in the glucagon receptor gene, Gcgr. Retinas of homozygotes, not heterozygotes, slowly loose sensitivity and degenerate. The late-onset, progressive degeneration will be studied with an array of behavioral anatomical, physiological, biochemical and molecular techniques to determine if the Gcgr-/- mouse is an appropriate model for further study. A supplemental diet will be tested for rescuing vision in Gcgr-/- mice. Potential medical benefits are (1) improved knowledge of how human central vision responds to metabolic stress, (2) improved counseling of diabetics about transient losses of central vision caused by over medication with insulin, and (3) a new mouse model for studying possible causes of some types of late-onset, degenerative retinal diseases such as age-related macular degeneration (AMD). [unreadable] [unreadable]